The invention provides compositions for the treatment of immunological diseases or inflammation, in particular, such diseases those are mediated by cytokines. The principal elements of the immune system are macrophages or antigen-presenting cells, T cells and B cells. Macrophages are important mediators of inflammation and also provide the necessary “help” for T cell/stimulation and proliferation. For example, macrophages make the cytokines IL-1, IL-6, IL-12 and TNF-α, all of which are potent pro-inflammatory molecules.
TNF-α is a pro-inflammatory cytokine produced by a variety of cell types and expressed on the cell surface as a 233-amino acid 26 kDa membrane-bound precursor protein. TNF-α converting enzyme (TACE) proteolytically cleaves of membrane-bound TNF-α and produces a mature, soluble cytokine of 17 kDa that exists as a non-covalently bound trimmer. The biological effects of TNF-α are intervened by two membrane-bound receptors, designated as p55 and p75. Unregulated production of TNF-α is associated with a number of pathological conditions including diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, psoriasis, spondylitic arthritis, rheumatoid arthritis, congestive heart failure and may other diseases. Thus the inhibitors of TNF-α are potentially useful in the treatment of a wide variety of diseases.
The cytokine IL-1β also participates in the inflammatory response. It stimulates thymocyte proliferation, fibroblast growth factor activity, and the release of prostaglandin from synovial cells. Elevated or unregulated levels of the cytokine IL-1β have been associated with a number of inflammatory diseases and other disease states, including but not limited to Alzheimer's disease, adult respiratory distress syndrome, allergy, asthma, anorexia, atherosclerosis and pain and inflammation resulting from strain, sprain, trauma, surgery, infection or other disease processes. Since overproduction of IL-1β is associated with numerous disease conditions, it is desirable to develop compounds that inhibit the production or activity of IL-1β.
IL-6 participates in the immune response, hematopoiesis and inflammation. It is a potent inducer of the hepatic acute phase response and is a powerful stimulator of the hypothalamic-pituitary-adrenal axis that is under negative control by glucocorticoids. IL-6 promotes the secretion of growth hormone but inhibits release of thyroid stimulating hormone. Elevated levels of IL-6 are seen in several inflammatory diseases, and inhibition of the IL-6 cytokine subfamily has been suggested as a strategy to improve therapy for rheumatoid arthritis (Carroll et al., Inflamm Res, 47:1-7, 1998). In addition, IL-6 has been implicated in the progression of atherosclerosis and the pathogenesis of coronary heart disease (Yudkin et al., Atherosclerosis, 148:209-14, 1999). Implicated in several disease states, it is highly desirable to develop compounds that inhibit IL-6 secretion.
IL-12 is a heterodimeric cytokine consisting of a p40 and a p35 subunit, with potent immunoregulatory properties, primarily released by antigen-presenting cells, dendritic cells, and monocytes/macrophages in response to bacterial product and immune signals. It enhances natural killer (NK)-mediated cytotoxicity and induces interferon-gamma (IFN-γ) production by NK cells and T lymphocytes. IL-12 plays a key role in promoting Th1 immune responses, demonstrated both in vitro and in vivo. Antibodies against IL-12 have been found to have beneficial effect in experimental models for autoimmune diseases that are Th1-driven, such as experimental allergic encephalomyelitis (EAE) and 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced chronics intestinal inflammation in mice, a model for human inflammatory bowel disease.
Collagen induced arthritis (CIA) of mouse is an experimental model for rheumatoid arthritis (RA) that can be induced in DBA/1 mice by immunization with heterologous native type II collagen (CII) emulsified in Freund's complete adjuvant (FCA). It has been recently demonstrated that IL-12 can replace Mycobacterium tuberculosis when immunizing DBA/1 mice with CII resulting in severe arthritis associated with enhanced IFN-γ production by ex vivo CII-stimulating spleen cells and an increased collagen-specific IgG2a antibody response (Stern, A. S., et al., Proc. Natl. Acad. Sci, 1990, 87, 6808). The blockade of IL-12 by administration of anti IL-12 MoAb was not able to prevent the onset of CIA but dramatically reduced the severity of the arthritis (Malfait, A. M., et al., Clin. Exp. Immunol., 1998, 111, 377-383).
Crohn's disease is characterized by increased production of IL-12 by antigen-presenting cells in intestinal tissue and interferon-γ and TNF-α by intestinal lymphocytes and macrophages (Fuss, I. J. et al, J. Immunol., 1996, 157, 1261; Parronchi, P., et al, Am. J. Pathol., 1997, 150, 823; Plevy, S. E. et al, J. Immunol., 1997, 159, 627). These inflammatory cytokines in turn induce and sustain the granulomatous inflammation and bowel-wall thickening that are hallmarks of Crohn's disease. In mice, administration of a monoclonal antibody against IL-12 can result in the resolution of established colitis and, if given at the time of induction of colitis, can prevent inflammation (Neurath, M. F. et al, J. Exp. Med., 1995, 182, 1281). Anti-IL-12 can also prevent and treat the spontaneous colitis seen in models of Th1-mediated inflammation such as mice that over express the human CD3ε gene and mice deficient in interleukin-10 (Simpson, S. J. et al, J. Exp. Med., 1998, 187, 1225).
Similar to IL-12, a related heterodemeric protein IL-23 consists of p19 and p40 subunits. A human antibody directed against p40 thus can effectively block the action of both IL-12 and IL-23. IL-12 and IL-23 are both produced by activated (mature) dendritic cells and are critical in promoting differentiation and proliferation of type 1 cytokine-producing naïve and memory T cells, respectively. The lesions of psoriatic skin shows the excessive presence of: (1) activated dendritic cells; (2) IL-23 and IL-12; and (3) type 1 cytokine-producing CD4+ and CD8+ memory T cells. Thus, the p40 subunit of IL-23/IL-12 is an attractive therapeutic target in psoriasis. Walter and coworkers (J. Exp. Med., 2001, 193, 339) have demonstrated that the cellular source of IL-12 and IL-12 p40 is inducible by viral infection, that there is a new functional consequence of IL-12 p40 production in vivo that is not dependent on actions of IL-12 p70 or IFN-γ, and provided the first proof that epithelial IL-12 p40 expression is abnormally programmed in asthma.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that afflicts around 1 million people worldwide. There is no medical treatment available so far that can cure MS. The pathogenesis of EAE/MS is a complex process that involves activation of macrophage/microglial cells, differentiation of encephalitogenic Th1 cells and secretion of inflammatory cytokines in the CNS. Interleukin-12 is produced mainly by macrophage/microglia that plays a critical role in the differentiation of encephalitogenic Th1 cells and pathogenesis of EAE and MS (Nararajan, C. and Bright, J. J., Genes and Immunity., 2000, 3, 59-70). This shows that IL-12 has a significant role in the pathogenesis of arthritis, multiple sclerosis, asthma, Crohn's disease, inflammatory bowel disease, psoriasis and related autoimmune diseases.
It will be appreciated from the foregoing that, while there have been extensive prior efforts to provide compounds for inhibiting, for example, TNF-α, IL-1β, IL-6 IL-12, or other agents considered responsible for inflammation or inflammatory diseases, e.g. arthritis, there still remains a need for new and improved compounds for effectively treating or inhibiting such diseases.